(Applicant's Abstract): The long-term goal of this research program is to thoroughly understand and to characterize the disposition and gastrointestinal absorption kinetics and bioavailabilty of the active chemical components of three extensively used botanicals: turmeric, ginger and boswellia. Furthermore, an understanding will be obtained of: the factors that affect absorption; absorption and metabolic interactions among those botanicals; the relationship between the pharmacokinetic and pharmacodynamic behavior of the active compounds. We hypothesize that our experimental design and the use of the Yucatan minipig will permit us to assess bioavailability and make predictions of that process in humans. Furthermore, we hypothesize that we will be able to develop useful and predictive pharmacokinetic/pharmacodynamic (PK/PD) models characterizing the anti-inflammatory responses to the botanical agents in pigs and apply that information to humans. The specific aims of this five-year project are: 1. Develop and/or adapt sensitive, selective and reproducible analytical methods for the quantitation in plasma of the putative active chemical compounds in the 3 botanicals and plasma metabolites. 2. Characterize the disposition kinetics of the pure, active chemical compounds (and metabolites) of the individual botanicals following intravenous (iv) dosing in Yucatan minipigs. 3. Characterize the gastrointestinal absorption (in the Yucatan minipig) and determine the absolute oral bioavailability of the active chemical compounds, from : i) a commercial form of each botanical, and ii) a capsule formulated to contain the pure chemical forms of the putative active ingredient. 4. Characterize the gastrointestinal absorption and absolute oral bioavailability (in the Yucatan minipig) of the active chemical compounds from a commercial form of each botanical as a function of dose. 5. Evaluate the potential pharmacokinetic interactions among these botanicals by combination dosing of commercial forms. 6. In conjunction with the pharmacokinetic information obtained from plasma samples, relate the in vitro anti-inflammatory responses obtained from those same samples and develop a pharmacokinetic/pharmacodynamic (PK/PD) model(s). This research project directly ties in with and benefits from the other research projects and core facilities in this Center proposal in the following ways. The Analytical Core facility (under Dr. Timmermann) will provide essential assistance in developing the needed analytical methods and in metabolite identification. Project 1 (Dr. Timmermann) will be responsible for the characterization of the botanicals and it will be through those efforts that an acceptable commercial form of each botanical will be identified for testing in this project in animals and in subsequent human clinical trials. The consultancy of Dr. Samuel Yalkowsky will permit us to formulate the active compounds into a solution and intravenous from. Furthermore, a significant aspect of Project 1 will provide in vitro anti-inflammatory biomarker measurements of the various fractions obtained from the botanicals as well as the pure chemicals (under the direction of Dr. Lantz). A significant aspect of this project is the pact that the blood samples obtained from the studies described in this project, will be submitted to Dr. Lantz for anti-inflammatory biomarker testing. The resulting data, for the first time to our knowledge, permit the development of PK/PD models to characterize the anti-inflammatory activity of the 3 botanical products to be tested. Those data and the creation of PK/PD models will benefit enormously from the consultancy of Dr. William J. Jusko who has developed and published extensively in the area of indirect response modeling. Finally, the data developed here will have a direct impact upon the human clinical trials planned (Dr. Nix), in that the same commercial form evaluated in the minipig will be employed in the human trial. We will be able to directly contrast the finding from the animal model to those obtained in humans.